- Preparation method of flumazenil
-
The invention discloses a preparation method of flumazenil, and belongs to the field of medicine synthesis. The method comprises the following steps: by taking 5-fluoro-2-nitrobenzoic acid as a raw material, carrying out condensation on 5-fluoro-2-nitrobenzoic acid and sarcosine ester, and then carrying out ring closing while reducing, so as to obtain 7-fluoro-3, 4-dihydro-4-methyl-1H-[1, 4] benzodiazepine-2, 5-diketone; and finally, carrying out halogenation and cycloaddition reaction to obtain flumazenil. According to the novel synthesis method of the flumazenil key intermediate 7-fluoro-3, 4-dihydro-4-methyl-1H-[1, 4] benzodiazepine-2, 5-diketone, provided by the invention, a green synthesis process is adopted, an intramolecular cyclization reaction is performed while a nitro group is reduced, and compared with a known flumazenil synthesis method, a strong oxidant, a highly toxic reagent (such as ethyl chloroformate) and the like are not needed, and the yield is higher.
- -
-
-
- Benzodiazepine derivative and preparation method and application thereof
-
The invention discloses a benzodiazepine derivative as shown in a formula (I), enantiomers, diastereoisomers, racemes and mixtures thereof, pharmaceutically acceptable salts, crystalline hydrates and solvates thereof, a preparation method thereof, and application of the derivative in the preparation of antidotes of GABAA receptor agonists, post-anesthesia awakening agents, anti-epileptic drugs, anti-senile dementia drugs, ethanol poisoning antidotes and awakening agents for treating consciousness loss caused by unknown reasons.
- -
-
Paragraph 0064; 0067; 0074-0077
(2021/07/10)
-
- Preparation method of high-purity flumazenil suitable for industrial production
-
The invention belongs to the technical field of medicine synthesis, and particularly relates to a preparation method of high-purity flumazenil suitable for industrial production. The flumazenil can beprepared by chlorination and ring closing. According to the preparation method disclosed by the invention, the industrial production time can be shortened, the equipment requirement is reduced, the economic benefit is maximized, and the purity of the obtained flumazenil is as high as 99.9%.
- -
-
Paragraph 0042; 0043; 0044
(2021/03/13)
-
- Facile aromatic radiofluorination of [18F]flumazenil from diaryliodonium salts with evaluation of their stability and selectivity
-
Aromatic radiofluorination of the diaryliodonium tosylate precursor with [18F]fluoride ions has been applied successfully to access [ 18F]flumazenil in high radiochemical yields of 67.2 ± 2.7% (decay corrected). The stability and reactivity of the diaryliodonium tosylate precursor plays a key role in increasing the production of 18F- labelled molecules under the fluorine-18 labelling condition. Various conditions were explored for the preparation of [18F]flumazenil from different diaryliodonium tosylate precursors. Optimum incorporation of [ 18F]fluoride ions in the 4-methylphenyl-mazenil iodonium tosylate precursor (5f) was achieved at 150°C for 5 min by utilizing 4 mg of the precursor, K2.2.2/K2CO3 complex, and the radical scavenger in N,N-dimethylformamide. This approach was extended to a viable method for use in automated synthesis with a radiochemical yield of 63.5 ± 3.2% (decay corrected, n = 26) within 60.0 ± 1.1 min. [ 18F]Flumazenil was isolated by preparative HPLC after the reaction was conducted under improved conditions and exhibited sufficient specific activity of 370-450 GBq μmol-1, with a radiochemical purity of >99%, which will be suitable for human PET studies. The Royal Society of Chemistry 2011.
- Moon, Byung Seok,Kil, Hee Seup,Park, Jun Hyung,Kim, Ji Sun,Park, Jimin,Chi, Dae Yoon,Lee, Byung Chul,Kim, Sang Eun
-
p. 8346 - 8355
(2012/05/04)
-
- An improved process for the synthesis of 4H-imidazo[1,5-a][1,4] benzodiazepines
-
The construction of CNS active imidazo[1,5-a][1,4]benzodiazepines has been improved in a one-pot annulation process. Georg Thieme Verlag Stuttgart.
- Yang, Jie,Teng, Yun,Ara, Shamim,Rallapalli, Sundari,Cook, James M.
-
experimental part
p. 1036 - 1040
(2009/12/01)
-
- Coded medication and methods of preparing same for identification and distinguishment
-
A selected substance is dissolved into a given injectable fluid medication having an initial clear visual appearance. The selected substance is selected from a group of substances which, when dissolved in the injectable fluid medication, will alter the clear appearance to produce a non-clear or altered visual appearance. The altered visual appearance could be a color, which, by code, identifies the given injectable fluid medication, and distinguishes the given injectable fluid medication from a different injectable fluid medication, the clear visual appearance of which has been altered by dissolving another selected substance to produce a colored visual appearance different from the color of the altered visual appearance of the given injectable fluid medication.
- -
-
-
- A concise and efficient synthesis of flumazenil and its precursor for radiolabeling with fluorine-18
-
Presently there is a strong interest in developing radioligands for in vivo imaging the GABAA-Bz site with positron emission tomography (PET). Flumazenil (1), a high-affinity GABAA-Bz site inverse agonist, is amenable for 11C and 18F-labeling. The current methods for synthesis of 1 and its precursor for 18F-labeling are not ideal and restrict structure-activity relationship (SAR) development. Herein we present a novel and less troublesome synthesis of 1 and its cognates to aid in the development of improved radioligands for PET imaging of GABAA-Bz site.
- Donohue, Sean R.,Dannals, Robert F.
-
supporting information; experimental part
p. 7271 - 7273
(2010/03/03)
-
- The isolation and use of a benzodiazepine iminochloride for the efficient construction of flumazenil
-
The benzodiazepine iminochloride 2 has been isolated, characterized and its reaction with a glycinate enolate synthon investigated resulting in an efficient synthesis of the imidazobenzodiazepine flumazenil.
- Rogers-Evans, Mark,Spurr, Paul,Hennig, Michael
-
p. 2425 - 2428
(2007/10/03)
-
- Process for the manufacture of imidazodiazepine derivatives
-
A process for the manufacture of compounds of formula STR1
- -
-
-
- Novel Benzodiazepine Receptor Partial Agonists: Oxadiazolylimidazobenzodiazepines
-
The synthesis and biochemical evaluation of a series of oxadiazole derivatives of imidazobenzodiazepines related to the benzodiazepine antagonist Ro 15-1788 (2a) are reported.Although the oxadiazole ring is seen as an isosteric replacement for the ester linkage, significant differences in structure-activity trends were observed.Specifically, oxadiazoles 9-12 invariably had increased receptor efficacy (as witnessed by measurements of the GABA shift) relative to the corresponding ester.Additionally, and in direct contrast to the classical agonists such as diazepam, affinity for the benzodiazepine receptor was enhanced by a 7- rather than 8-halo substituent.The results are discussed in terms of a six-point receptor-binding model originally based on the X-ray structure of 2a.For comparison, the crystal structures of two representative oxadiazole derivatives, 10h and 12o, having a 6-oxo and 6-phenyl group, respectively, were determined and the data incorporated into a modified binding model to account for the greater efficacy of these compounds.It is concluded that the antagonist behavior of 2a relies upon the hydrogen-bond-acceptor properties of the ester carbonyl oxygen whereas for the oxadiazole series this site is localized at the imidazole nitrogen.
- Watjen, Frank,Baker, Raymond,Engelstoff, Mogens,Herbert, Richard,MacLeod, Angus,et al.
-
p. 2282 - 2291
(2007/10/02)
-
- Imidazodiazepine derivatives
-
Imidazodiazepine derivatives of the formula STR1 wherein A together with the two carbon atoms denoted as α and β is selected from the group consisting of STR2 the dotted line represents the double bond present in groups (a) and (b), D is >C O or >C S, R 1 is selected from the group consisting of cyano, lower alkanoyl and a group of the formula --COOR 4, R 4 is selected from the group consisting of methyl, ethyl, isopropyl and 2-hydroxyethyl, R 5 is selected from the group consisting of hydrogen, trifluoromethyl and halogen and R 6 is selected from the group consisting of hydrogen, trifluoromethyl, halogen and lower alkyl and either R 2 is hydrogen and R 3 is hydrogen or lower alkyl or R 2 and R 3 together are trimethylene or propenylene and the carbon atom denoted as γ has the S- or R,S-configuration, and pharmaceutically acceptable salts thereof are presented and have utility for antagonizing the central-depressant, muscle relaxant, ataxic, blood pressure-lowering and respiratory-depressant properties of 1,4-benzodiazepines which have tranquillizing activity. They can be used, for example, as antidotes in the case of intoxications in which excessive intake of 1,4-benzodiazepines which have tranquillizing participates, or for shortening an anaesthesia induced by such 1,4-benzodiazepines. They can also be used for suppressing the activities on the central nervous system of 1,4-benzodiazepines used in other fields of indication, for example of schistosomicidally-active 1,4-benzodiazepines such as (+)-5-(o-chlorophenyl)-1,3-dihydro-3-methyl-7-nitro-2H-1,4-benzodiazepin-2-one.Also presented are processes to produce the imidazodiazepine derivatives and intermediates therefor.
- -
-
-
